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A novel isoform of microphthalmia-associated transcription factor inhibits IL-8 gene expression in human cervical stromal cells.
Li, Xiang-Hong; Kishore, A Hari; Dao, Doan; Zheng, Weiming; Roman, Christopher A; Word, R Ann.
Afiliação
  • Li XH; Division of Reproductive Endocrinology and Urogynecology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9032, USA.
Mol Endocrinol ; 24(8): 1512-28, 2010 Aug.
Article em En | MEDLINE | ID: mdl-20573688
Cervical ripening during pregnancy is a profound change in cervix structure and function characterized by increases in the proinflammatory cytokine IL-8 and dissolution of the cervical extracellular matrix. Relatively little is known about the molecular mechanisms that underlie these events. Here, we report identification of a novel isoform of micropthalmia-associated transcription factor in human cervical stromal cells (MiTF-CX) that is down-regulated 12-fold during cervical ripening and that represses expression of IL-8. Ectopic expression of MiTF-CX in human cervical stromal cells resulted in substantial suppression of endogenous IL-8 mRNA and protein expression, whereas expression of dominant negative MiTF-CX mutants with impaired DNA binding resulted in dramatic increases in IL-8 production. Gel shift, reporter gene, and chromatin immunoprecipitation assays revealed one strong binding site (E-box (-397) CACATG(-391)) in the human IL-8 promoter that was crucial for mediating transcriptional repression by MiTF-CX. Moreover, we show that MiTF-CX expression in the cervix was itself positively autoregulated via two E-box motifs within a 2.1-kb promoter fragment. We therefore propose that maintenance of cervical competency during pregnancy is an active process maintained through suppression of IL-8 by the transcription factor MiTF-CX. During cervical ripening, loss of MiTF-CX would result in significant up-regulation of IL-8 mRNA and protein synthesis, thereby leading to recruitment and activation of leukocytes within the cervix and dissolution of the extracellular matrix.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Colo do Útero / Interleucina-8 / Células Estromais / Isoformas de Proteínas / Fator de Transcrição Associado à Microftalmia Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Female / Humans / Pregnancy Idioma: En Ano de publicação: 2010 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Colo do Útero / Interleucina-8 / Células Estromais / Isoformas de Proteínas / Fator de Transcrição Associado à Microftalmia Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Female / Humans / Pregnancy Idioma: En Ano de publicação: 2010 Tipo de documento: Article